RESEARCH Open Access Thyroid function in children with … … · · 2017-08-29ing”...

RESEARCH Open Access

Thyroid function in children with growthhormone (GH) deficiency during the initial phaseof GH replacement therapy - clinical implicationsJoanna Smyczynska1,2, Maciej Hilczer1,2, Renata Stawerska1,2, Andrzej Lewinski2,3*

Abstract

Background: Normal thyroid hormone secretion or appropriate L-thyroxine (L-T4) substitution is necessary for theoptimal effect of the growth hormone (GH) administration on growth rate. The decrease of free thyroxine (FT4)levels at recombinant human GH (rhGH) therapy onset has been reported in several studies. The aim of thepresent study was to evaluate the effect of rhGH administration on thyrotropin (TSH) and FT4 serum concentrationsin children with GH deficiency (GHD) during the 1st year of therapy, as well as to assess potential indications tothyroid hormone supplementation in them.

Patients and methods: The analysis involved data of 75 children (59 boys, 16 girls) with disorders of GH secretion(GHD, neurosecretory dysfunction - NSD) and partial GH inactivity (inactGH), who were treated with rhGH for - atleast - one year. In all the children, body height and height velocity (HV) were assessed before and after 1 year oftherapy, while TSH, FT4, IGF-I and IGFBP-3 before treatment and after 3-6 months and 1 year of treatment. In thepatients, who revealed hypothyroidism (HypoT), an appropriate L-T4 substitution was introduced immediately. Theincidence of HypoT, occurring during the initial phase of rhGH therapy, was assessed, as well as its influence onthe therapy effectiveness.

Results: Before rhGH substitution, there were no significant differences in either auxological indices or TSH and FT4secretion, or IGF-I concentration and its bioavailability among the groups of patients. During the initial 3-6 monthsof rhGH administration, a significant decrease of FT4 serum concentration, together with a significant increase ofIGF-I SDS and IGF-I/IGFBP-3 molar ratio was observed in all the studied groups. In 17 children, HypoT wasdiagnosed and L-T4 substitution was administered. Despite similar IGF-I secretion increase, the improvement of HVpresented significantly lower in children with HypoT than in those who remained euthyroid all the time.

Conclusions: The incidence of HypoT during the initial phase of GH treatment in children with GHD and thenegative effect of even transient thyroid hormone deficiency on the growth rate should be taken into account.

BackgroundGrowth hormone (GH) deficiency (GHD) in childrenwith short stature is an unchallenged indication to thetherapy with recombinant human GH (rhGH). Themain goal of the treatment is to increase patients’ heightvelocity (HV) and to improve the attained final height(FH). The most important peripheral mediator of GHactivity is the insulin-like growth factor-I (IGF-I). Theinsulin-like growth factor binding protein-3 (IGFBP-3) is

the main carrier protein binding to IGF-I in plasma,thus determining its bioavailability. Besides, either nor-mal thyroid hormone secretion or appropriate substitu-tion of L-thyroxine (L-T4) is necessary for the optimaleffect of both endogenous GH and rhGH substitutionon the growth rate.The relationships between GH secretion and thyroid

function, as well as the effects of rhGH administration onthyroid hormone levels have been the subject of numer-ous studies. The data of Cacciari et al. [1], presented 30years ago, indicated that the risk of inducing an alterationin thyroid function in hypopituitary patients duringrhGH therapy was only slight and that the abnormal

* Correspondence: [email protected] of Endocrinology and Metabolic Diseases, Polish Mother’sMemorial Hospital - Research Institute, Lodz, Poland

Smyczynska et al. Thyroid Research 2010, 3:2http://www.thyroidresearchjournal.com/content/3/1/2

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values of thyroxine (T4) and triiodothyronine (T3)returned to normal limits during follow-up. Next, Gácsand Bános [2] reported that rhGH therapy in childrenwith idiopathic GHD reduced T4 secretion and affectedthe peripheral metabolism of thyroid hormones, resultingin an increase of T3. In 1994, Jørgensen et al. [3] reportedthat, in GH-deficient adults, rhGH administration stimu-lated peripheral T4 to T3 conversion in a dose-dependentmanner and influenced circadian rhythm of thyrotropin(TSH) secretion. Moreover, in some of those patientsbefore rhGH administration, serum T3 levels were sub-normal despite T4 substitution and normalised duringthe therapy. As it was shown that rhGH administrationmight induce a fall in serum T4, it seemed probable thatGHD could mask secondary hypothyroidism in somepatients with hypopituitarism. Recently, Agha et al. [4]proved that rhGH administration really led to „unmask-ing” hypotyroidism in hypopituitary adults. Similar werethe observations of Losa et al. [5], who reported that, inadults with GHD, administration of rhGH therapy wasassociated with a significant decrease of free T4 (FT4) infirst 6 months of treatment.First reports, concerning the effects of rhGH therapy

on thyroid hormone levels in children also confirmed anincrease of extrathyroidal conversion of T4 to T3 duringthe therapy [6]. Conversely than described for adults [5],as early as in 1994, Laurberg et al. [7] stated that chil-dren with GHD, evaluated thoroughly to exclude sec-ondary thyroid failure before rhGH administration, didnot develop hypothyroidism during rhGH substitution.Up to now, several interesting studies have been pub-

lished on long-term effects of rhGH replacement ther-apy on thyroid function, both in adults [8-10] and inchildren [11-18].The aim of current study was to evaluate the effect of

rhGH substitution on TSH and FT4 serum concentra-tions in children with GHD during the 1st year of ther-apy, as well as to assess potential indications to thyroidhormone supplementation in them.

Patients and methodsThe retrospective analysis involved the data of 75 chil-dren (59 boys, 16 girls) with GHD, who were qualified torhGH therapy. At therapy onset, the patients’ height wasbelow the 3rd centile, according to Polish referencecharts [19], HV was slow (below -1.0 SD/year), bone agewas delayed, according to Greulich-Pyle’s standards [20].Thyroid function was normal in most of children(67 cases). In the remaining 8 patients, L-T4 supplemen-tation had been administered, due to either hyperthyro-tropinemia or relatively low (normal but close to thelower limit of reference range) FT4 concentration andpharmacological euthyrodism was then confirmed. In allthe children IGF-I and IGFBP-3 secretion was measured

in a single blood sample during in morning hours. Inmost of the children, IGF-I concentration was eitherdecreased or close to lower limit of normal range. Itshould be mentioned that - though IGF-I is the main per-ipheral mediator of GH action - children with normalIGF-I secretion may be diagnosed as GH-deficient andqualified to rhGH therapy in the light of current nationalrecommendations, enclosed in the programme of therapyof GHD in children with rhGH [21]. In all the patients,nocturnal GH secretion was assessed during 3 hoursafter falling asleep (5 samples every 30 minutes from the60th to the 180th minute) and 2 stimulating tests wereperformed (with clonidine 0.15 mg/m2 orally and withglucagon 30 μg/kg, not exceeding 1 mg, i.m.). The diag-nosis of GHD was established when GH peak duringnocturnal assessment and in both stimulating tests wasbelow 10 ng/ml. Neurosecretory dysfunction (NSD) wasdiagnosed in children with normal results of stimulatingtests but decreased nocturnal GH secretion (that obser-vation had to be confirmed by documenting decreasedGH secretion in prolonged, 6-hour nocturnal profile). Inchildren with decreased IGF-I secretion and normal GHpeak (both in nocturnal profile and after pharmacologicalstimulation), IGF-I generation test was performed afterexclusion of other causes of IGF-I deficiency, not relatedto GH secretion disorders and GH action (like malab-sorption syndromes, liver diseases, malnutrition, othersevere chronic diseases). Interestingly enough, a goodresponse to rhGH administration - at least, twofoldincrease of IGF-I secretion, leading to normalisation ofits level in plasma - was observed in each case, thusallowing exclusion of GH insensitivity and pointing atdecreased bioactivity of endogenous GH in these chil-dren. The obtained results of that test supported the indi-cations to rhGH administration in them. Children witheither other hormonal deficiencies or severe and/orchronic, growth influencing diseases, as well as thosewith acquired GHD, were not included to the studiedgroup. All the girls had normal female karyotype.At rhGH therapy onset, patients’ age was 12.2 ± 2.4

years (mean ± SD). The therapy with rhGH in a dose of0.21 ± 0.02 mg (0.63 ± 0.05 IU)/kg/week was adminis-tered for, at least, 1 year. In every patient, TSH and FT4

concentration was assessed three times: before the firstrhGH injection, after 3-6 months and at after 1 year oftreatment; all the blood samples were taken in morninghours. Additionally, IGF-I and IGFP-3 concentrationswere measured at the same time points and IGF-I stan-dard deviation score (SDS) for age and sex, as well asIGF-I/IGFBP-3 molar ratio was calculated.Plasma TSH and FT4 concentrations were measured by

the electroimmunochemiluminescent method (ECLIA),Roche, Elecsys®Systems 1010/2010/modular analyticsE170. For TSH, analytical sensitivity was 0.005 μIU/ml,


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range - up to 100 μIU/ml, intra-assay coefficient of var-iance (CV) - 1.5-8.6%, accuracy - 1.1-3.0%. Analyticalrange for FT4 was 0.023-7.77 ng/dl, intra-assay CV - 1.4-2.9%, accuracy - 2.7-6.6%.Growth hormone concentrations were measured by

hGH Immulite, DPC assay, calibrated to WHO IRP 80/505 standard, with analytical sensitivity up to 0.01 ng/ml,calibration range up to 40 ng/ml, sensitivity of 0.01 ng/ml,intra-assay CV - 5.3-6.5% and inter-assay CV - 5.5-6.2%.Both IGF-I and IGFBP-3 concentration was assessed by

Immulite, DPC assays. For IGF-I, WHO NIBSC 1st IRR87/518 standard was applied, with analytical sensitivity20 ng/ml, calibration range up to 1600 ng/ml, intra-assayCV - 3.1-4.3% and inter-assay CV - 5.8-8.4%. For com-parison among children of different age and sex, IGF-Iconcentrations were expressed as IGF-I SDS, accordingto DPC reference data. The assay for IGFBP-3 assessmentwas calibrated to WHO NIBSC Reagent 93/560 standard,with analytical sensitivity 0.02 μg/ml, the calibrationrange up to 426 μg/ml, the intra-assay CV - 3.5-5.6% andthe total CV - 7.5-9.9%. For calculation of IGF-I/IGFBP-3molar ratio, the following molecular masses were used:7.5 kDa for IGF-I and 42.0 kDa for IGFBP-3 [22]. Forcomparison among children with different age and sex,IGF-I concentrations were expressed as SD score (IGF-ISDS), according to DPC reference data.Statistical analysis included comparison of thyroid func-

tion (FT4 and TSH concentrations), IGF-I secretion(as IGF-I SDS) and its bioavailability (expressed as IGF-I/IGFBP-3 molar ratio) in particular time points, before andduring rhGH therapy. Non-parametric Wilcoxon’s test fordependent samples was applied, as the distribution of theanalysed parameters (assessed with Kolmogorov-Smirnov’stest) presented not consistent with normal distribution.The differences among particular subgroups of patients inthe same time point were assessed with non-parametricKruskall-Wallis’ test for independent samples. The level ofstatistical significance was at p < 0.05.

ResultsBefore rhGH substitution, there were no significant dif-ferences in either auxological indices or TSH and FT4

secretion, or IGF-I concentration and its bioavailabilityamong the groups of patients with GHD, NSD andinactGH. Moreover, all the differences among thegroups at particular time points (i.e. both after 3-6months and after 1 year of rhGH therapy) still remainedinsignificant, except for significantly lower TSH ininactGH than in both GHD and NSD after 1 year ofrhGH treatment (see Table 1). Interestingly enough, thechanges in FT4 and TSH concentration were similar inchildren with previously normal thyroid function(67 cases) and in those on L-T4 substitution at rhGHtherapy onset (8 cases). Detailed comparisons of the

Table 2 Selected auxological and hormonal data ineuthyroid vs. previously L-T4 treated patients

euthyroid L-T4 treated p

n 67 8

Before rhGH administration

age [years] 12.3 ± 2.2 10.8 ± 3.6 0.15

height SDS -2.65 ± 0.54 -3.13 ± 0,76 0.07

HV [cm/year] 3.6 ± 0.9 3.8 ± 1.0 0.71

TSH [mU/l] 2.42 ± 0.91 2.18 ± 1.02 0.27

FT4 [ng/dl] 1.26 ± 0.15 1.30 ± 0.15 0.97

IGF-I SDS -2.00 ± 0.98 -2.23 ± 1.72 0.87

IGF-I/IGFBP-3 0.18 ± 0.06 0.19 ± 0.11 0.97

After 3-6 months of rhGH therapy

TSH [mU/l] 2.68 ± 1.38 2.75 ± 0.74 0.52

FT4 [ng/dl] 1.12 ± 0.13 1.17 ± 0.37 0.16

IGF-I SDS 0.49 ± 0.83 0.16 ± 1,30 0.29

IGF-I/IGFBP-3 0.39 ± 0.11 0.31 ± 0.13 0.21

After 1 year of rhGH therapy

HV [cm/year] 9.8 ± 2.1 11.7 ± 1.1 0.01

TSH [mU/l] 2.14 ± 0.90 2.94 ± 1.98 0.27

FT4 [ng/dl] 1.29 ± 0.16 1.21 ± 0.22 0.55

IGF-I SDS 0.67 ± 0.77 0.61 ± 1.31 0.72

IGF-I/IGFBP-3 0.42 ± 0.11 0.37 ± 0.15 0.64

Table 1 Selected auxological and hormonal data of thepatients with respect to the initial diagnosis

Diagnosis p

GHD NSD inactGH

n 36 23 16


age [years] 12.0 ± 2.4 12.0 ± 2.9 12.9 ± 1.4 0.56

height SDS -2.59 ± 0.53 -2.91 ± 0.68 -2.68 ± 0.49 0.57

TSH [mU/l] 2.42 ± 0.91 2.18 ± 1.02 2,63 ± 0.94 0.69

FT4 [ng/dl] 1.31 ± 0.13 1.28 ± 0.17 1.29 ± 0.15 0.45

IGF-I SDS -1.77 ± 0.92 -2.18 ± 1.23 -2.36 ± 1.06 0.58

IGF-I/IGFBP-3 0.21 ± 0.08 0.16 ± 0.05 0.16 ± 0.05 0.31


TSH [mU/l] 2.80 ± 1.28 2.60 ± 1.20 2.56 ± 1.60 0.77

FT4 [ng/dl] 1.13 ± 0.17 1.13 ± 0.19 1.13 ± 0.13 0.73

IGF-I SDS 0.33 ± 0.99 0.40 ± 0.89 0.33 ± 0.74 0.38

IGF-I/IGFBP-3 0.38 ± 0.13 0.37 ± 0.11 0.38 ± 0.11 0.86


TSH [mU/l] 2.51 ± 1.23 2.15 ± 0.74 1.56 ± 0.45 0.005

FT4 [ng/dl] 1.29 ± 0.18 1.27 ± 0.18 1.27 ± 0.13 0.72

IGF-I SDS 0.78 ± 0.88 0.62 ± 0.69 0.45 ± 0.83 0.72

IGF-I/IGFBP-3 0.43 ± 0.12 0.41 ± 0.11 0.39 ± 0.09 0.86


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above-mentioned groups of children are presented inTable 2. Among the patients who had L-T4 substitution,administered before rhGH therapy onset, the decreaseof FT4 below the lower limit of normal range wasobserved in 2 out of 8 cases and in those children, anincreased dose of L-T4 was necessary to restore euthyr-oidism. A significant decrease of FT4 serum concentra-tion was observed during the initial 3-6 months ofrhGH administration, together with insignificantincrease of TSH in all the studied groups, as well as inparticular subgroups of patients. For more detailed datasee Table 1 and Figure 1 and Figure 2.Simultaneously, a significant increase of IGF-I SDS

was observed not only on the 3-6th month of rhGH

therapy, with respect to pre-treatment values, but alsoafter 1 year of therapy vs. the values obtained on the3-6th month of treatment. Significant differences inIGF-I SDS in particular time points were observed forall the subgroups, expect for that between the values onthe 3-6th month and after 1 year in the subgroup withinactGH. Similarly, a significant increase of IGF-I/IGFBP-3 molar ratio was observed on the 3-6th monthof rhGH therapy, with respect to pre-treatment values,however, with only a very slight further increase (insig-nificant) after 1 year of therapy, both in all the studiedgroups and in the subgroups of patients. The moredetailed data are presented in Figure 3 and Figure 4.Interestingly enough, there were no significant

Figure 1 Free thyroxine serum concentrations before and during rhGH therapy in particular subgroups of patients with respect to theinitial diagnosis.


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Figure 2 Thyrotropin secretion before and during rhGH therapy in particular subgroups of patients with respect to the initialdiagnosis.

Figure 3 IGF-I secretion (expressed as IGF-I SDS for age and sex) before and during rhGH therapy in particular subgroups of patientswith respect to the initial diagnosis.


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differences in either IGF-I SDS or IGF-I/IGFBP-3 molarratio, observed among the particular subgroups of chil-dren at any time point (see Table 1).According to our observations, the therapy with rhGH

led to a similar increase of IGF-I secretion and of itsbioavailability in the patients with different forms of dis-orders of GH secretion and activity. During the initialphase of rhGH replacement therapy, a transient decreaseof FT4 concentration was observed in all the subgroupsof patients, in most subjects being connected with anincrease of TSH secretion. Spontaneous normalisationof FT4 concentration on the level close to the valuesobtained before rhGH administration, observed in themajority of patients, presented parallel to furtherincrease of IGF-I secretion.In 17 children, out of 67 previously untreated with L-

T4 (25.4%), either FT4 concentration decreased belowthe lower limit of normal range (8 cases) or TSHincreased above the upper limit of the normal range (8cases), or both (1 case). In those patients, L-T4 therapywas administered just after the diagnosis of hypothyroid-ism was established, in the initial daily dose of 25 μg,individually adjusted under control of TSH and FT4

levels. In the remaining 50 patients, TSH and FT4 con-centrations returned to pretreatment values at the endof the 1st year of rhGH administration. Thus, in all the

children both TSH and FT4 concentrations after 1 yearof rhGH therapy were normal. It should be remindedthat all the children were euthyroid at rhGH therapyonset.In the patients, in whom hormonal evaluation after

3-6 months of rhGH administration led to the diagnosisof HypoT (at least in subclinical form), TSH levels weresignificantly higher, while FT4 concentrations - signifi-cantly lower than in those children who remainedeuthyroid during rhGH administration. There were nosignificant differences between them in either IGF-I SDSor IGF-I/IGFBP-3 molar ratio at that time point. More-over, after 1 year of rhGH administration there were nosignificant differences either in IGF-I secretion or inIGF-I/IGFBP-3 molar ratio between the groups of chil-dren who were euthyroid all the time and the other one,grouping children who required L-T4 substitution. How-ever, it should be emphasized that TSH and FT4 levelsin all of them were normal at the latter time point.Nevertheless, some differences between the groups wereobserved and should be mentioned. Surprisingly, IGF-ISDS presented lower (however only insignificantly) inthose children who remained euthyroid during all thestudy period, than in those, who presented withhypothyroidism after 3-6 months of rhGH replacement.Another important observation was a further increase of

Figure 4 IGF-I bioavailability (expressed as IGF-I/IGFBP-3 molar ratio) before and during rhGH therapy in particular subgroups ofpatients with respect to the initial diagnosis.


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IGF-I SDS in both groups after 1 year of therapy withrespect to the values obtained after 3-6 months. Never-theless, after 1 year of rhGH therapy, HV improvement(expressed both as the difference and as the ratiobetween HV during and before the therapy) was signifi-cantly lower in those children who were hypothyroideven for a relatively short period of time during theinitial phase of rhGH therapy. It should be stressed thatL-T4 substitution was administered as soon as possiblewhen hypothyroidism was diagnosed. For detailed datasee Table 3 and Figure 5, Figure 6 and Figure 7.

DiscussionThe phenomenon of T4 and FT4 concentration decreaseafter rhGH administration in GH-deficient subjects hasbeen reported in several studies [1,2,5,9,12,14]. Also, thereturn of thyroid function to baseline during follow-uphas been quite well documented [13,15,17,18]. Ourresults confirm previous observations, concerning theseproblems.Moreover, it has been suggested that rhGH therapy

might disclose previously unrecognised thyroid insuffi-ciency rather than induce hypothyroidism [4,7,14]. Thedata, concerning the development of central

hypothyroidism in terms of rhGH substitution, seem to berather scarce and non-consistent. In 2007, Agha et al. [7]stated that GHD masked central hypothyroidism in a sig-nificant proportion of hypopituitary adults. Conversely, in2008, Lose et al. [5] reported only a low incidence ofhypothyroidism in GH-deficient adults on rhGH substitu-tion. Similar were the observations of Laurberg et al. [7]and Giavoli et al. [16] in GH-deficient children, beginningrhGH therapy. In our study, in 15% of previously euthyr-oid children, a decrease of FT4 level with no adequateincrease of TSH was observed, (it should be stressed thatchildren with evident central hypothyroidism before rhGHadministration, being a component of multiple pituitaryhormone deficiency, were not included in current study).Thus, our observations confirm the phenomenon of„unmasking” central hypothyroidism after rhGH therapyadministration in some of children with previous diagnosisof isolated GHD. Changes in TSH secretion during initialperiod of rhGH substitution are less evident than fluctua-tions of FT4 concentration. Most researchers reportedeither a lack of significant changes in TSH secretion[1,4,6,9,14,16,18] or a decrease of TSH level in terms ofrhGH administration [8,15,17]. The last phenomenon hasbeen explained by an increase of somatostatin (being anatural TSH inhibitor) in the patients on rhGH therapy[15]. In our study, the mean TSH serum concentrationpresented a slight increase, followed by a recovery to pre-treatment level. It seems that the differences among theresults obtained in different studies might be related todifferent study protocols and analysed time points.The most frequently quoted mechanism of changes in

thyroid hormone levels is GH-mediated increase of per-ipheral T4 to T3 deiodination [7-9,12,14]. Moreover, apotential role of IGF-I in stimulating that process has beensuggested by Jørgensen et al. [9]. The relationshipsbetween GH, IGF-I and thyroid hormone secretion havebeen subject of numerous studies. More than 25 years ago,in 1983, Chernausek et al. [23] documented that plasmasomatomedin C (i.e. IGF-I) concentrations were dimin-ished in hypothyroid patients, however, the pathogenesisof this phenomenon remained unclear. Either diminishedGH secretion or direct effects of hypothyroidism uponsomatomedin production were considered. In early 1990s,Näntö-Salonen et al. [24] stated that the mechanisms ofthyroid hormone action on the insulin-like growth factorsystem were not GH-mediated. Similar were the observa-tions of Inukai et al. [25], concerning the patients withautoimmune thyroid diseases. In 2003, Iglesias et al. [26]stated that hypothyroidism is associated with significantreductions of IGF-1 and IGFBP-3. Next, Purandare et al.[27] documented that in infants with hypothyroidism bothtotal and free IGF-I levels were lower than those in healthyones and increased significantly after L-T4 therapy, whilein older children with acquired hypothyroidism they were

Table 3 Selected auxological and hormonal data of thepatients according to thyroid function during rhGHadministration

euthyroid hypothyroid p

n 50 17


age [years] 12.4 ± 2.3 12.3 ± 2.1 0.94

height SDS -2.60 ± 0.50 -2.77 ± 0.63 0.38

HV [cm/year] 3.5 ± 1.0 3.8 ± 0.9 0.14

TSH [mU/l] 2.22 ± 0.95 2.65 ± 0.92 0.05

FT4 [ng/dl] 1.33 ± 0.15 1.21 ± 0.11 0.01

IGF-I SDS -2,01 ± 0.97 -1.99 ± 1.00 0.45

IGF-I/IGFBP-3 0.19 ± 0.07 0.18 ± 0.05 0.71


TSH [mU/l] 2.25 ± 0.92 3.71 ± 1.75 < 0.001

FT4 [ng/dl] 1.16 ± 0.10 1.01 ± 0.14 < 0.001

IGF-I SDS 0.37 ± 0.81 0.54 ± 0.81 0.59

IGF-I/IGFBP-3 0.38 ± 0.11 0.42 ± 0.12 0.36


TSH [mU/l] 2.07 ± 0.98 2.16 ± 0.79 0.54

FT4 [ng/dl] 1.31 ± 0.15 1.23 ± 0.14 0.11

IGF-I SDS 0.61 ± 0.67 0.83 ± 0.83 0.35

IGF-I/IGFBP-3 0.41 ± 0.09 0.45 ± 0.12 0.84

HV [cm/year] 10.0 ± 2.1 9.3 ± 2.0 0.23

ΔHV [cm/year] 6.5 ± 2.3 5.4 ± 2.1 0.01

ΔHV [%] 213 ± 118 154 ± 85 0.05


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not significantly lower than in age- and sex-matched con-trols. However, during L-T4 treatment an increase of totalIGF-I but not of free IGF-I was observed. Similarly, Bonaet al. [28] documented that in the patients with hypothyr-oidism - both congenital and caused by thyroiditis - L-T4

replacement led to physiological increase of IGF-I andIGFBP-3 secretion. Moreover, Schmid et al. [29] showedthat, during L-T4 replacement, IGF-I and acid-labile

subunit secretion increased in the patients with both pri-mary and central hypothyroidism, while IGFBP-3 - only inthose with primary hypothyroidism. In 2008, Akin et al.[30] reported that GH-IGF axis was affected in thepatients with subclinical hypothyroidism and that L-T4

replacement therapy could prevent abnormalities relatedto GH-IGF axis in them. Moreover, at the same time, Soli-man et al. [31] proved that, in children with neglected

Figure 5 IGF-I secretion (expressed as IGF-I SDS for age and sex) before and during rhGH therapy in the patients divided according tothe thyroid function during the initial phase of rhGH administration.

Figure 6 IGF-I bioavailability (expressed as IGF-I/IGFBP-3 molar ratio) before and during rhGH therapy in the patients dividedaccording to the thyroid function during the initial phase of rhGH administration.


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congenital hypothyroidism, even after long period ofhypothyroidism, L-T4 replacement improved the growthrate, leading to a partial recovery of GH-IGF-I axis.In our study, differences were found between the

improvement of the growth rate in the patients with nor-mal thyroid function and in those with even transienthypothyroidism. As a matter of fact, a direct effect of thyr-oid function on IGF-I secretion was not fully confirmed inour study, as there were no significant differences in anincrease of IGF-I secretion between the euthyroid childrenand those, who presented with hypothyroidism duringrhGH administration. However, further increase of IGF-Isecretion on the same rhGH dose was observed after 1year of rhGH therapy, with respect to the values obtainedafter 3-6 months of treatment. This phenomenon mightbe explained either by the improvement of thyroid func-tion (i.e. recovery to pre-rhGH-treatment values of FT4

and TSH) or by the appropriate L-T4 substitution.Obligatory L-T4 supplementation from the beginning

of rhGH therapy in euthyroid patients has not beenrecommended [17] due to a little evidence for the devel-opment of clinically significant hypothyroidism in mostof previously euthyroid patients [13] and spontaneousrecovery to pre-treatment thyroid function in mostcases [13,15,17,18].

Our findings speak for the important role of maintain-ing euthyroid status of the patients for the best effective-ness of rhGH therapy, as even short-term, transienthypothyroidism presented to be a cause of lowerincrease of HV in 1st year of rhGH administration.Thus, the incidence of revealing (or “unmasking”)hypothyroidism should be taken into account, whilestarting rhGH administration, as hypothyroidism mayworsen the response to the therapy. It seems that eitherearlier assessment of TSH and FT4 concentration afterrhGH therapy onset or L-T4 administration from thebeginning of rhGH therapy in children with normal butrelatively low FT4 secretion and/or normal but relativelyhigh TSH levels should be taken into account. Furtherstudies seem necessary to fully assess the influence ofthyroid function (and thyroid hormone substitution) onthe effectiveness of rhGH therapy in children with disor-ders of GH secretion. It seems also important to estab-lish - if possible - the threshold values of pre-rhGH-treatment TSH and/or FT4 levels predictive for revealinghypothyroidism during rhGH administration.

ConclusionsThe incidence of HypoT during the initial phase ofrhGH treatment in children with GHD and the negative

Figure 7 Height velocity increase in the 1st year of rhGH therapy in the patients divided according to the thyroid function during theinitial phase of treatment.


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effect of even transient thyroid hormone deficiency ongrowth rate should be taken into account while begin-ning rhGH administration in them.

AbbreviationsCV: coefficient of variance; FH: final height; FT4: free thyroxine; GH: growthhormone; GHD: growth hormone deficiency; HypoT: hypothyroidism; HV:height velocity; IGF-I: insulin-like growth factor-I; IGFBP-3: insulin-like growthfactors binding protein-3; L-T4: L-thyroxine (levothyroxine); NSD:neurosecretory dysfunction; inactGH: growth hormone inactivity; RhGH:recombinant human growth hormone; SDS: standard deviation score; T3:triiodotyronine; T4: thyroxine; TSH: thyrotropin.

Author details1Department of Paediatric Endocrinology, Medical University, Lodz, Poland.2Department of Endocrinology and Metabolic Diseases, Polish Mother’sMemorial Hospital - Research Institute, Lodz, Poland. 3Department ofEndocrinology and Metabolic Diseases, Medical University, Lodz, Poland.

Authors’ contributionsJS participated in acquisition of data, performed the statistical evaluationand drafted the manuscript, MH participated in acquisition of data and indesign of the study, RS participated in acquisition of data, AL conceived ofthe study, participated in its design and revised the text of manuscript. Allauthors read and approved the manuscript.

Authors’ informationAL - Professor; Head of Chair of Endocrinology and Metabolic Diseases,Medical University of Lodz, Poland, Head of Department of Endocrinologyand Metabolic Diseases, Polish Mother’s Memorial Hospital - ResearchInstitute. MH - Ass. Professor; Head of Department of PediatricEndocrinology, University of Lodz, Poland. JS - PhD, MD, endocrinologist. RS- PhD, MD, endocrinologist.

Competing interestsThe authors declare that they have no competing interests.

Received: 16 February 2010 Accepted: 22 March 2010Published: 22 March 2010

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doi:10.1186/1756-6614-3-2Cite this article as: Smyczynska et al.: Thyroid function in children withgrowth hormone (GH) deficiency during the initial phase of GHreplacement therapy - clinical implications. Thyroid Research 2010 3:2.

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